The phosphotidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway encompasses a number of signaling points which are critical in the control of cell growth and survival. AKT, also known as protein kinase B, is a serine-threonine protein kinase which has a key role in this pathway. Activation of AKT is mediated by PI3K. PI3K generates phospholipids which bind to AKT. Upon binding, AKT is recruited to the plasma membrane and is activated through phosphorylation. AKT activation and signaling promotes cell survival, growth and proliferation. Increased AKT activation has been implicated in a wide variety of cancers. P70 S6 kinase is a serine-threonine protein kinase which is a downstream effector of the PI3K/AKT/mTOR signaling pathway. P70 S6 kinase phosphorylates the ribosomal protein S6 in cells and regulates ribosome biogenesis, cell growth and cell cycle progression in response to mitogenic stimulation. P70 S6 kinase is commonly activated in many solid tumors.
A series of substituted piperidine compounds having AKT inhibitory activity are disclosed in WO 2008/075109. These compounds are disclosed for use in the treatment of diseases or conditions comprising or arising from abnormal cell growth or abnormally arrested cell death, including cancer. There remains a need to provide alternative AKT inhibitors which can be used in the treatment of proliferative disorders such as cancer. The present invention provides alternative AKT inhibitors. Preferred compounds of the present invention are more potent AKT inhibitors than those known in the art.
Additionally, there is a need to provide alternative p70 S6 kinase inhibitors which can be used in the treatment of proliferative disorders such as cancer. The present invention provides alternative p70 S6 kinase inhibitors. Preferred compounds of the present invention are more potent p70 S6 kinase inhibitors than those known in the art.
Preferred compounds of the present invention are inhibitors of both AKT and p70 S6 kinase. More preferred compounds of the present invention are more potent AKT inhibitors than known AKT inhibitors and more potent p70 S6 kinase inhibitors than known p70 S6 kinase inhibitors.
Certain compounds of the present invention have lower hERG activity than AKT and/or p70 S6 kinase inhibitors known in the art.